The texaphyrins are aromatic pentadentate macrocyclic "expanded porphyrins" which have been found to be useful as MRI contrast agents, as radiosensitizers and in photodynamic therapy (PDT). Texaphyrin is considered as being an aromatic benzannulene containing both 18.pi.- and 22.pi.-electron delocalization pathways. See, e.g., Sessler, J. L. et al., Accounts of Chemical Research, 1994, 27, 43. Texaphyrins and water-soluble texaphyrins and method of preparation have been described in U.S. Pat. Nos. 4,935,498; 5,252,720; 5,256,399; 5,272,142; and 5,292,414; and in U.S. application Ser. No. 08/196,964; all of which are incorporated herein by reference. The aromatic free-base texaphyrins and texaphyrin metal complexes are produced by the oxidation and (for the metal complex) metallation of a reduced nonaromatic macrocycle precursor (the "sp.sup.3 " compound).
On an industrial scale, crystallization or precipitation are preferred methods for purification and isolation of solids such as texaphyrin-metal complexes and the nonaromatic (sp.sup.3) precursors. Other techniques such as extractions do not provide texaphyrins in solid form, and chromatographic techniques are also less practical and often cost-prohibitive on a production scale.
Existing methods for texaphyrin-metal complex isolation have employed organic solvent mixtures such as heptane-ethyl acetate at ambient to slightly-elevated temperatures. Nonaromatic (sp.sup.3) macrocycles have been isolated from a variety of organic solvents such as isopropanol-heptane mixtures at -23.degree. C. (where the use of very low temperatures is cumbersome and impractical for large-scale manufacturing) or octanol at 25.degree. C. (which requires special processing to remove the residual higher boiling solvents) or other organic solvents. For both classes of compounds, water has been avoided. The sp3 macrocycle is not stable in water, consistent with the known properties of molecules with imine bonds (the macrocycle has two such bonds). For a large number of metal-texaphyrin complexes, the water solubility of the complex precludes isolation from an aqueous system, and very poor results have been encountered with mixed aqueous-organic systems for these compounds.
The present invention addresses these deficiencies and allows aqueous-based isolation procedures to be used for these classes of compounds. Water is a highly desirable solvent due to its low cost, low toxicity, and lack of flammability. Waste disposal of aqueous materials may be expected to be preferable to organic waste streams. Another advantage of the present invention is the use of temperatures near ambient conditions, moderated by the use of ice or simple refrigeration systems. Such techniques are more practical on an industrial scale than prior techniques.